Joint and Tissue Repair – Enough to Make You “GAG”

Joint and tissue health is an important topic among many people, especially athletes. Supplements such as glucosamine, chondroitin, MSM, and other products are often taken when there is joint pain or degeneration, in hopes that a cure can be found in a bottle. Sometimes these substances work and sometimes they don’t. Some research says they may help, other studies say otherwise. But whether you should take these supplements or not for your joint pain or injury is not the point of this article, but rather what brought you to even consider taking such a supplement is. You see, you’re supposed to make these compounds naturally in your body every day, and even consume some of them in the foods you should be eating. But first, a little bit of biochemistry to get you up to speed…

GAGS: Glycosaminoglycans

Making new connective tissue is all about something called GAGs. That stands for glycosaminoglycans which are primarily a bunch of sugar molecules linked together. They come from what is known as the glycolytic pathway – that’s the same pathway you use to make energy from sugar in your body.

Connective tissue is fibrous tissue found throughout your body in the form of tendons, and the framework of fibers in muscles, ligaments, bone, cartilage, and even blood and lymph tissue. Connective tissue not only connects body tissue together, but it protects organs and even stores energy. All tissues in the body, with the exception of teeth, can be repaired. Some tissue, such as liver tissue and bone, can even be regenerated.

Glucosamine’s Role in Tissue Repair

In order to make GAGs you need the main precursor, which is glucosamine. Glucosamine is high in the shells of shellfish as well as animal bones, which is why our grandparents who used to make soup with the animal bones in the pot received many of the necessary bone-building nutrients we lack today because most of us just buy the broth. But you also make glucosamine naturally through the glycolytic pathway (mentioned previously) with nutrients such as vitamins B1, B2, B3, and B5, as well as magnesium, lipoic acid, and potassium. Glutamine, which is an amino acid our bodies can synthesize, is also necessary and added into this step. Let’s learn more!

Glutamine

Glutamine is the most abundant naturally occurring, non-essential amino acid. It’s been shown to be useful in the treatment of serious illnesses, injury, trauma, and burns. Glutamine is also used by many athletes as a supplement because evidence indicates that glutamine may increase plasma human growth hormone levels by stimulating the pituitary gland, which in turn increases muscle growth. A healthy individual has plenty of glutamine.

Chondroitin’s Role in Tissue Repair

Now when this glucosamine is linked to a protein it can form substances called proteoglycans, such as chondroitin and eventually into chondroitin sulfate, which is an important component of cartilage. Much of chondroitin is made up of more sugar molecules and glucuronic acid, another amino acid. This amino acid is primarily used in a process called glucuronidation which is how your body (primarily the liver) detoxifies certain drugs, pollutants, hormones (especially cortisol and estrogen), and other substances. Magnesium, manganese, vitamin B2, and vitamin C are all needed here in order to make this work. Artichokes are naturally high in glucuronic acid. Yum.

So we’re getting there. We have the amino acid glutamine and the glycolytic pathway working well so we’ve made glucosamine. Then we’ll will bring it down to make chondroitin as long as our liver hasn’t used up all our glucuronic acid dealing with a lot of detoxification. Next, we need some sulfur.

Sulfation and Tissue Health

Sulfation is very important as sulfur is needed to make glucosamine sulfate and chondroitin sulfate which helps facilitate cartilage repair. The amino acid L-cysteine is very high in sulfur and can sometimes be of great benefit as a supplement, and it’s also high in protein-rich foods like eggs and whey protein. Sulfates are high in foods such as broccoli, cauliflower, garlic, cabbage, onions, radishes, and mustard. Proper levels of magnesium, vitamin B12, vitamin B6, (in its active form of pyrodixal-5-phosphate), and folic acid, (also typically in its active form of 5-MTHF), are also needed for proper sulfation. Sulfation, like glucuronidation, is another major liver pathway and very necessary for the detoxification of hormones and drugs, especially NSAIDs. *Note, sulfa, which is a classification of drugs that many people are allergic to, is not the same thing as sulfur, the element.

Methylsulfonylmethane (MSM) is a biologically available source of sulfur, like the amino acid cysteine. MSM is a metabolite of dimethylsulfoxide (DMSO). DMSO is a solvent and is readily absorbed into the skin so it is often used as a drug delivery system. DMSO, a byproduct of paper manufacturing, was banned for some time by the FDA and allowed only in veterinary medicine, primarily equine vet care. It’s high in sulfur, which is why it can help with tissue repair and is known for its distinctive smell – some say it smells like garlic, others say rotten milk, and I’ve even heard old socks. You will stink! I can attest to the smell first-hand as I used DMSO a lot throughout my high school and college years as I was always injured. Skin burns are also very common using DMSO especially if it’s mixed with a NSAID and then applied directly to the injured area, as many athletes do.

So if you are having joint pain or a connective tissue problem, especially the common cartilage degeneration, what do you do? Do you take glucosamine sulfate? Chondroitin sulfate? MSM? DMSO? Cysteine or glutamine? Taking all the nutrients I just mentioned won’t be practical, and multi-supplements won’t work. It’s more important to realize how you got to the point of even seeking out these supplements in the first place, and what you can do to possibly reverse and prevent further tissue and joint degeneration. Let’s look at the anatomy of an injury to understand this more.

Stress and Joint Problems

Chronic stress is the cause of most injuries. You do not just wake up one day with a sore knee or neck; and you do not “catch” ITB syndrome or pull a hamstring one day while running because you just overdid it on that particular day. You sure don’t all of a sudden develop “bone-on-bone” joint problems or joint degeneration. Chronic stress, whether from overtraining, lack of sleep, ingestion of too much caffeine or refined sugar, or an emotionally unstable job or relationship, leads to hormonal imbalances. The hormone cortisol increases as a result. This decreases tissue insulin sensitivity – a phenomenon termed “insulin resistance.” It is very important because it leads to the decreased absorption of glucose into the body’s cells. When glucose doesn’t enter the cells, not only is energy production impaired, but joints ultimately cannot be repaired due to the inability to make GAGs, as discussed previously.

In insulin resistance, the cells are starving for sugar that is sitting right outside the doorway in the bloodstream waiting to be let in, and often you will crave sweets. You may crave something sugary throughout most of day, and usually right after a workout or a low carbohydrate meal. You may be irritable and moody from the roller coaster blood sugar levels hitting more highs and lows than most Internet stocks of early 2000. Over time, your muscles may start to spasm or cramp up. You may also experience what some physicians describe as “restless leg syndrome” and other sleep problems related to blood sugar dis-regulation. Insomnia and waking up frequently are very common too.

So in order to properly make the glycolytic pathway work so you have glucose available to make glucosamine you obviously have to monitor and deal with your stress levels. High stress = high cortisol = decreased glucose absorption = inability to make glucosamine = an injured athlete. This may mean training more aerobically rather than anaerobically, cutting down caffeine, getting more sleep, adjusting your life or work schedule; you get the idea. Diet plays a huge role here too. More protein, healthy fats (fish, grass fed beef, flax, eggs, avocado, nuts, seeds, coconut, butter, olive oil), and a low grain and sugar diet will help you use fat primarily as a fuel allowing the body to focus on making glucosamine and GAGs. That means the less stress you’re under and the healthier you eat, the healthier your joints will be! I think a Paleo-Type Diet is great to implement here. This GAGs process is not just inhibited by cortisol, but also estrogen as well as certain drugs such as anticoagulants, immune-suppressive agents, and antibiotics. Ladies, that means you’re more susceptible to joint issues than us guys, due to your estrogen levels, and you’ll be even more at risk if you take birth control pills or other hormonal replacement drugs.

When it comes to repairing an injury, or making sure an injury doesn’t surprise you tomorrow, you’ve also got to have sulfation and glucuronidation working well for you as I’ve talked about. So remember that glucuronidation has to do with liver detoxification of hormones, drugs, and other pollutants. So the less environmental stress you’re under (think air pollution, for example), the less medications you take, and the less cortisol you make (because you’ve dealt with stress levels), the more you have glucuronidation working for you. Now for the sulfation part…

Sulfates as a reminder, are present in foods such as broccoli, cauliflower, garlic, cabbage, onions, radishes, and mustard. But more importantly, sulfates are also depleted during high stress levels too because they are needed to detoxify cortisol in the liver. Do you see a pattern here? I sure hope so. If you are under a lot of stress then cortisol really makes a mess of every part of this GAGs pathway! The key is to not deplete more sulfur than you take in. Interesting is the fact that NSAIDs restrict sulfate availability, so cartilage cannot be repaired. This is a shocking fact for many people who are trying to help their injury with these drugs, (aspirin and ibuprofen) yet are actually doing more harm than good by depleting their sulfate levels. Research shows that NSAIDs are only beneficial 2-3 days after injury. Taking them longer, or for the many that take them every day, is inviting greater problems later in life. Deficiency of the trace mineral molybdenum also inhibits sulfate availability.

Once glucose is available, because it was allowed inside the cells since you’ve managed your stress, (normal cortisol levels), your body can make glucosamine and then ultimately make chondroitin, which will happen because you’ve got good glucuronidation going on. This all looks for the sulfur, (which is present when there are also low stress levels and no signs of NSAID abuse), to make chondroitin sulfate – the ultimate prize in injury repair. And of course we needed some glutamine along the way but we have plenty of that because a healthy individual naturally makes more than enough and is getting some in their diet – beef, chicken, fish, eggs, dairy products, cabbage, beets, beans, spinach, and parsley.

The big idea here is actually very simple in such a complex way. You have to embrace a healthy lifestyle because it all is going to affect the health of your tissues and joints. Make sure your diet contains some of the foods mentioned so you have the resources available to make GAGs happen. Consider looking at individual nutrients you may be deficient in to help you repair your tissue. Deal with your excess stress whether that’s adjusting your training, diet, or lifestyle. If you take one of the joint/cartilage supplements and it benefits you that’s fine as it may be very necessary to get you going in the right direction; it’s better than taking some drug to deal with your problem, but you should still investigate why you aren’t making the substance on your own to truly fix your health problem. The GAGs lesson is over.

Comments

Yet another extremely valuable post by Dr. Gangemi. The internet makes it possible to disseminate so much mistruth and hype (usually with an ulterior motive) and it is refreshing to know there are still people like Dr. Gangemi out there who care about our long term well being, health and do not seek to profit from it. While Dr. Gangemi does make a very nice living through his practice, this is but one example of how he gives back with no expectation of anything in return. Thank you Dr. Gangemi.

So, would you think that if I am eating Paleo (8 mo now) and running barefoot and aerobically (using Maffetone’s MAF heartrate), I don’t need to be taking the Glucosamine/Chondroitin I’ve taken for years? (49 yo female with history of arthritis and osteoporosis in the family — starting to feel pain in my feet upon waking about 10 yrs ago, that’s when I started taking Gluco/Chond).

Correct, in a general sense there should be no reason to take it anymore, unless you have a specific nutrient deficiency. For example, did you notice how I mentioned the active form of folic acid? 5-Methyltetrahydrofolate (5MTHF) is what your body is supposed to convert folic acid into when you take it and it’s the form found naturally in fruits and veges. But most people don’t eat enough fruits and veges to get their necessary amounts AND it is known that at least 10-15% of the population have a genetic mutation that does not allow them to fully make 5MTHF, and 20-30% of the population is said to have a single gene mutation which makes it more difficult for them to make 5MTHF. So, in this case a person may not be making enough cartilage repairing tissue because they aren’t methylating their folic acid (B12 too) correctly. So if they don’t get enough naturally from their diet or from taking 5MTHF (not the typical folic found in most supplements), then there could be issues. Other genetic issues can occur to making it necessary for individuals to need certain nutrients more than others.

One more point – an important one I did not address in the post. Taking this stuff month after month, especially year after year is not healthy. I have seen numerous patients react to these supplements, most often with problems in their pancreas (blood sugar metabolism – makes sense as you learned from reading the post). So don’t think that more is better. It isn’t. And definitely don’t think that if it doesn’t work then it won’t cause a problem, because it very well could be, especially after all those years.

That is interesting. I must say, I’ve definitely taken the “it can’t hurt” approach. My problem now is that I am working as a volunteer and where I live, it is very expensive. This month, I’m skating on the edge of running out of food. So buying an expensive supplement that might not be necessary doesn’t seem wise. I think I’ll finish what I have and then stop it for awhile and see what happens.

Vitamin C for another day, but I don’t use or recommend the highly synthetic and isolated form of vitamin C we are all familiar with and are told is “vitamin C” – ascorbic acid. It’s best in its whole, natural form with all its cofactors as found in whole foods, and some whole food supplements too.

I think I have one of those genetic mutations you speak of (Ehlers Danlos syndrome). I’ve been going Paleo for a few months and have seen a significant reduction in pain. But I wonder if my body is capable of rebuilding itself thanks to my faulty genetics. Supplementation doesn’t really work for me because my system is very sensitive and I react badly to most of them. Do you have any experience with collagen disorders and/or have any suggestions?

Other than the suggestions I note in the post, it would be hard to advise where to look in a more specific case for you. Yes, I’ve seen some people with collagen disorders and like you, they tend to do much better with a Paleo-Type diet. Lots of antioxidants from fruits, veges, and herbs are a must too. I’m not sure how much you can rebuild, if any, but I’m sure you can limit (perhaps significantly) the disorder by living as much of a healthy life as you possibly can.

Doc! What a great post! Every day I hear “Well, I’m getting old, I guess I’ll just have pain”, but that is the furthest anyone will go to take responsibility for their health. No one wants to give up the things that are making them sick! Health doesn’t come in a bottle. It comes from taking control of your life in finances, employment, exercise, and diet. Treat your human vehicle with respect, and it takes you the places you want to go with no complaints.

It is important to watch cholesterol levels when taking Glucosamine supplements, as some people do have increases in cholesterol levels when taking it. Personally, my total cholesterol jumped over 30 points when taking Glucosamine supplements, and returned to normal when I stopped taking the product. I think this is relatively rare, but still worth watching.

Thanks Greg, I assume you’re referring to LDL cholesterol which would make sense as, per my response to one of the other comments, glucosamine can cause blood sugar issues, which in turn, will negatively affects cholesterol levels by oxidizing LDLs. Not a good thing.

This is so interesting, and neatly explains my own experience.
I had the beginnings of a DuPutrens contracture on my left hand, and it had begun to progress towards the ‘cording’ stage. Around this time I was diagnosed with Pre-diabetes and I understand that Dupuytrens contracture is regarded as an indicator of incipient Diabetes. (My Mom is a Type 2 Diabetic and she has a Dupuytrens contracture too).
I started eating Paleo about 4 months ago, and along with weight loss, increased energy and improved blood sugar control, I’m certain the Dupuytrens contracture is resolving!
I had thought I must be imagining it, but now I know that my body is healing itself. Thanks so much for the information.

That’s awesome Fiona, I love to hear when people take their health into their own hands (no pun intended!). Many extremity problems are linked to dysglycemia, such as hand numbness (especially when sleeping), carpal tunnel, and Raynaud’s “Disease”. Even a slight tingling in the fingertips when exercising is a sign of blood sugar imbalances.

You mentioned that anticoagulants can interfere with the GAG’s process. My father had a heart attack at the age of 41…from the outside he appeared to be in perfect shape…he had low cholesterol…but was under a lot of stress at work at the time. This happened 10 years ago. He is now off of all statins (typical treatment even though he didn’t have cholesterol issues) and most of the other drugs (not sure what these were), but he is still required to take coumadin, an anticoagulant. This is because he originally went off of everything (including the coumadin) a year after his heart attack, and a few months later, he had to go to the hospital because a clot had formed in his damaged ventricle (the blood was just pooling there because the heart is no longer able to pump there). The doctors decided it was best that he stay on the coumadin indefinitely. Now he complains of sore joints, stiff legs, etc. Is there anything that can counter the effects of the coumadin on this process without reducing the benefits it has for preventing clots? I don’t think he will be able to go off the coumadin unless his heart can be repaired, but hopefully he can become more mobile than he is now. He loves being active, but the joint pain and stiffness really prevent him from being able to do these things.

Hi Primalpal, thanks for comment. I just saw a guy last week in a similar situation. His cholesterol was 118 and he was taking Lipitor for prevention. It’s a bit crazy how things are viewed sometimes. You know I’m happy to stick my neck out here a bit at times offering people some advice that they’re not going to get from anyone else, but this is a tough one. I don’t need anyone dying, or even coming close. The issue here is that you have to be careful not to negate the effects of the coumadin, (rat poison) but only its side-effects. The whole coagulation cascade is very complex; it’s a lot more complex than most of us know. I’ve had some PhD coagulation experts explain to me how it all integrates in the body and my head was spinning for days. You see, you can take products like fish oil, but its anti-coagulation affects are not exactly the same as the principles that coumadin works off of. There are other products out there, such as lumbrokinase, (Boluoke), that can help as they are fibrinolytic agents. I’d check out this lab called Esoterix, as they specialize in coagulation panels and can often provide more insight rather than just the blanket treatment of “stay on coumadin” based off results and a knowledgeable doctor who understands coagulation. Then the other issue to consider is properly detoxifying the liver as many of drug side-effects are due in part to sluggish livers. I’m not recommending going to the store to go on some crazy liver flush diet or supplements (or to take fish oil or Boluoke either), but to find a more naturally based doc who can help him with these issues and perhaps run a more comprehensive lab test as mentioned. Shoot me an email if you’d like and perhaps I know someone out by you guys if you’re not close to SockDoc Ville’ Good luck.

Just followed the link over from Mark’s Daily Apple. Amazed that I understood all the biochem, great job explaining it so all can get it. Was just tickled that you KNOW the history on DMSO. It seems usually people don’t know what it is, where it’s from, or how it has been used for so long. Can’t wait till they use it IV in people. Only saying that because it has been run IV in Equines as a last ditch effort and brought the horses out of the woods.
Now I just need to use up the mineral supplement I have that includes MSM with Glucosamine. Then switch to the stuff that is just minerals. (Still working on eating a better diet… until I get that leveled out, the minerals seem to help fill in the gaps.)

Thanks Lizzie B! They already do use it in IVs! I once went in a local MDs office who uses it in his patients and I could literally taste it when I walked in the door. The guy getting the IV drip was 3 rooms back! The doc thought it was pretty funny that I knew he had the drip going just from opening the front door.

Thanks Brian. Yes the same issues do apply for a couple important reasons. One is that the outside of the disc (called the annulus fibrosus) is made up of thick collagen fibers that hold the inner nucleus intact. So the health of that area is important with GAGs. The other is that disc issues often result from poor biomechanics – muscle imbalances and joint dysfunctions either directly or indirectly affecting the disc. Manganese is perhaps the most important nutrient needed for our spinal discs.

Yes, both NSAIDs and cortisol can and will impair healing. Taking NSAIDs, especially when you don’t need them, can cause a chemical reaction in your body that will create 10 to 100 times more inflammation than the original inflammatory reaction you may be trying to fight. This is called a leukotriene reaction. Cortisol injections are known to impair GAGs synthesis and result in joint weakness.

I am in “WOW” but not finished the article let alone the posts! TCM ( chinese medicine) links the liver with joint problems. But I have never found any other corroborative info!
I have history of tendon / ligament damage since taking up running 35 years ago, orthotics for 32, MCS for 30 years and recent diag. of pre-diabetes (insulin resistance).
I have dealt with these piecemeal as the holistic practitioners were not holistic enough! I have been on glutamine supplements for the liver abnormality for 5 years- personally i think they stimulate appetite. But did not prevent current foot injury! We really have to understand that we have to remove the bad things as well as put in the good things. Piecemeal cannot work.
I so agree with your views Mr SocDoc !!!

I was wondering if you have any recommendations for Morton’s Neuroma. I injured BOTH feet this past January and have had 1 Cortisone shot, TENS, ultrasound, and massage therapy all to no avail. I started in June taking serrapeptase, B-50, and Tumeric.Curcumin which seems to have provided some relief, however, if I am walking for any length of time over a half hour the cramping nerve pain returns. I amalso receiving HPLT (high powered laser treatment) once a week that supposedly will help. What is your take on these modalities? I am terrified of the ‘alcohol shots’ an or thee surgery the podiatrist mentioned if conservative measures failed; it being only 70% effective. I don’t like those odds!!

Hello Doc! Thank you for this article! It helped me tweak some things I’m doing…add some other…subtract a few…been working on healing the cortisol thing for a while…years and years and years of cumulative stress-shock-obesity-trauma (you get the picture)…much more in tune with what’s going on now yet still have a significant way to go. Was on tremendous western meds (huge variety) and now on none…liver was damaged and had spots…off all meds 6+ months (a 3 year process)…last liver test came out healthy and clean (per the western doc). Thank you thank you thank you for your awareness and life experience and for sharing all of this…

1st and foremost, thank you so much for creating such a comprehensive and informative website. it has helped me SO much through my recent injury. i wish i could see you in person but i’m all the way in san diego, ca.

what do you think about osteo bi flex & it’s ingredients (i read the side effects, and based on my family history/personal history, im pretty sure im safe):

in 2008 an MRI stated i have intense bone marrow edema, chondral fissuring, interruption of subchondral bone plate @ the end of the big toe proximal phalanx. my 2008 flare up was pretty bad (it prevented dorsi flexion). 2010 it flared up mildly. 2012 it flared up lightly. i noticed that there was a correlation with eating foods high in uric acid too, my blood tests confirmed that i had slightly high uric acid levels to which im now taking allipurinol. i never had a gout outbreak though. i have been going 2-3 years strong of increasing my diet to alot of fruit/veggies/no gluten. i take fish oils daily. ive also been controlling my stress alot.

main reason for inquiring about osteo bi flex is that i want to thicken the cartilage at the end of the proximal phalanx since there was intense wear and tear in 2008 and i’ve had mild flare ups since. if you do not recommend osteo bi flex, is there any supplement out there that can increase my cartilage and create healthiness between my 1st meta and proximal phalanx of my big toe? thank you so much dr gangemi!

I would never take anything from Costco; I don’t trust them and there’s usually a reason their supplements are so cheap.

When I use (give to a patient) either glucosamine or chondroitin, they typically only get one bottle because I’m more concerned with the substrate(s) they are most likely missing to make the final product. That’s different for everybody – one person I might give manganese, another B12, and another magnesium.

And of course you have to clean up your diet which usually means dealing with insulin issues, so the cartilage no longer becomes inflamed and can hopefully heal.

Hi up until 6 years ago the only thing I have had done was my gall bladder removed. Then I broke my leg ,and had to have it plated. Since that everything seems to have gone wrong. I have had a torn rotor culf in my right shoulder, laser treatment on my throat (nodule build up) had the plates removed then to top it of last year stepped awkward and popped my acl in my right knee. and my cartilage flipped over inside my knee.. Had the acl repaired, cartilage taken out and having a monovisc injection in my knee next week… oh and I am a fitness instructor who loves her job…
Can you please recommend if there is any supplements I should be taking.
Than you
Andrea Jones

Thanks for the post doc. I believe In what you are saying. I was recently told I have two disk protrusions in lumbar. I was hurt while training jiu jitsu-as I was put in body lock. Disks are showing signs of degeneration. Pain is mild without exercises. When I exercise I get increased pain and tightness. I went through heavy break up and am a pretty stressed worried individual. I usually handled this stress via excercise. I have been a vegetarian my whole life,I am currently 27. My Pt gave me McKenzie stretches for my posterior bulges along with sstretches. I am going to purchase glucosomine and chondroitin in hopes of slowing or arresting disk degeneration. You say that stretching is bad. Do you have any advice? Obviously I need to destress. Having a “degenerative” condition doesn’t help. Thanks very much for your time.

Some supplement claims that thier supplement provides necessary nutrition for body to produce glucosamine. I like to know how much supplement is sufficient for body to produce enough glucosamine for the body? will there be a case that the body cannot produce glucosamine or little amount of glucosamine even with ample supply of the necessary nutrition?
Is it possible that the body may have difficulty to produce glucosamine? What will be the causes? Is age one of the causes? How to find out if the body having this difficulty?
If body is having difficulty to produce glucosamine, what can be the solution? Take the ready made glucosamine pill like Viatril-s or bio-calth?
Thank you very much.

That’s a very involved question as for the supplement, it depends on how well it is manufactured. I use some glucosamine products, but often give my patients the precursors to make it within their body.

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Sock-Doc.com is a health and fitness website intended to educate individuals about injury treatment and prevention as well as other health related issues. The information presented on this site gives general advice on health care and fitness aspects and is not intended to treat, diagnose, prescribe, or replace any health care visit. The entire contents of this website are based upon the opinions of Dr. Gangemi, "Sock Doc", unless otherwise noted. Sock-Doc is intended to share knowledge and information from the research and experience of Dr. Gangemi and his community. Dr. Gangemi encourages you to make your own health care decisions based upon your research along with your qualified health care professional.